Chiral synthesis of thienamycin from D-glucose

ABSTRACT

Disclosed is a chiral, total synthesis of thienamycin from D-glucose which proceeds via intermediates I, II and III to known aldehyde IV which is known to be useful in the total synthesis of thienamycin (V): ##STR1## wherein: R is lower alkyl having 1-6 carbon atoms or bi-valent alkyl having 2-6 carbon atoms which joins the two sulfur atoms; R 1  is lower alkyl or aralkyl, such as benzyl and the like; and R 2  is hydrogen or a removable protecting group, such as triorganosilyl wherein the organo groups are independently selected from lower alkyl, phenyl and phenylloweralkyl.

This is a division of application Ser. No. 464,185, filed Feb. 7, 1983,now U.S. Pat. No. 4,448,976, issued 5-15-84, which in turn is a divisionof application Ser. No. 248,177, filed Mar. 30, 1981 and now U.S. Pat.No. 4,384,998 issued May 24, 1983.

BACKGROUND OF THE INVENTION

This invention relates to the chiral, total synthesis of thienamycinfrom D-glucose (dextrose).

In its broadest terms, the process proceeds from glucose viaintermediates I, II, and III and encounters aldehyde IV which is knownto be useful in the total synthesis of thienamycin (V). ##STR2##wherein: R² is hydrogen or a removable protecting group such as atriorganosilyl group wherein the organo moieties are independentlyselected from alkyl having 1-6 carbon atoms, phenyl, and aralkyl having7-14 carbon atoms; R¹ is a lower alkyl having 1-6 carbon atoms, oraralkyl, for example, methyl, ethyl, propyl, benzyl, and the like; R islower alkyl or the two sulfur atoms may be joined to form a ringcomprising R.

The transformation IV→V is known. See, for example, U.S. patentapplication Ser. No. 112,058 filed Jan. 14, 1980. To the extent that thecited U.S. patent application discloses the utility of intermediatespecies IV and its transformation to thienamycin, it is herebyincorporated by reference. Also incorporated by reference for the samepurpose are U.S. Pat. No. 4,234,596 (issued 11/18/80); and EPOApplication No. 79101307.1 filed 5-1-79, Publication No. 0007973.

Also incorporated by reference are the following concurrently filed,commonly assigned U.S. patent application of Philippe L. Durette Ser.No. 248,175 now U.S. Pat. No. 4,415,731; Ser. No. 248,178 now U.S. Pat.No. 4,348,325; Ser. No. 248,176 now U.S. Pat. No. 4,131,982, and Ser.No. 248,174 now abandoned. (all filed Mar. 30, 1981). All of theseapplications relate to the synthesis of thienamycin from D-glucose.

As will be made evident from the Detailed Description of the Inventionwhich follows, the presently disclosed and claimed process ischaracterized by several advantages. Most noteworthy is that thestarting reagents for the process are inexpensive and safe to handle.The process is characterized by being conducted under moderateconditions which are amenable to scale up and by a sequence of stepswhich are individually high yielding. It should be further noted that inmany of the sequences the intermediates need not be isolated so thatindividual sequences or distinct process steps may be conducted in asingle pot.

DETAILED DESCRIPTION OF THE INVENTION

The process of the present invention may conveniently be represented bythe following reaction diagram: ##STR3##

Diagram I is discussed below. In preface to Diagram I, however, itshould be noted that thienamycin (V) is an exceptionally potent, broadspectrum β-lactam antibiotic, particularly notable for its activityagainst Pseudomonas sp. and its resistance to β-lactamases. The absolutestereochemistry of thienamycin (V) ##STR4## is 5R, 6S, 8R. The presentinvention comprises a chiral, total synthesis of thienamycin startingfrom the readily available sugar, D-glucose (dextrose) (VI). The 5R, 6S,8R stereochemistry of thienamycin is inherent in the D-glucosestructural symmetry, as depicted in VI (chiral centers 3, 4 and 5).D-glucose is functionalized to afford optically active azetidinonealdehyde IV, via intermediates I, II, and III. Compound IV, above, isknown to be useful in the total synthesis of thienamycin.

A key intermediate in the conversion of D-glucose into azetidinonealdehyde IV is methyl 3-azido-2,3,6-trideoxy-α-D-arabino-hexopyranoside(I). Compound I is transformed into methyl3-azido-4-C-cyano-2,3,4,6-tetradeoxy-α-D-arabinohexopyranoside (II),which is then converted, as depicted in the diagram above, into the openamino ester dithioacetal III and subsequently into azetidinone aldehydeIV.

Methyl 3-azido-2,3,6-trideoxy-α-D-arabinohexopyranoside (4) is obtainedeither from methyl 2,6-dideoxy-α-D-arabino-hexopyranoside (3) or frommethyl α-D-glucopyranoside (12), as represented by the followingreaction diagrams, respectively: ##STR5##

Methyl 2,6-dideoxy-α-D-arabino-hexopyranoside (3) is obtained fromD-glucose (1), via 2-deoxy-D-glucose (13), or D-glucal (14), and methyl2-deoxy-α-D-glucopyranoside (2), as represented by the followingreaction diagram: ##STR6## Methyl α-D-glucopyranoside (12) is obtainedfrom D-glucose (1) as shown below, ##STR7##

Now, returning to Diagram I, above, the transformation 1→2 is known.Typically D-glucose (1) is converted into methyl2-deoxy-α-D-glucopyranoside (2) by the following sequence of reactions:(a) acetic anhydride and pyridine or acetic anhydride and sodium acetateto give penta-O-acetyl-D-glucopyranose; (b) hydrogen bromide in aceticacid to afford tetra-O-acetyl-α-D-glucopyranosyl bromide; (c) zinc andacetic acid to yield tri-O-acetyl-D-glucal; (d) sodium (or sodiummethoxide) in methanol to give D-glucal; and (e) methanolic hydrogenchloride to yield 2. Conversion of D-glucal (or 2-deoxy-D-glucose) into2 is reported in I. W. Hughes, et. al., J. Chem. Soc., 2846 (1949).

The transformation 2→3 is accomplished by treating 2 in a solvent suchas toluene, benzene, dimethylformamide, dichloromethane, or the likewith an iodinating agent (or other halogenating agent), such asmethyltriphenoxyphosphonium iodide, iodotriphenoxyphosphonium iodide,triphenyphosphine-N-iodosuccinimide; triphenylphosphinetetraiodomethane;triphenylphosphine-2,4,5-triiodoimidazole; triphenylphosphine, iodine,and imidazole; or the like at a temperature of from 20° to 100° C. forfrom 1 to 24 hours.

The hydrogenolysis to yield compound 3 is typically conducted in asolvent, such as methanol, ethanol, ethyl acetate, or the like, at atemperature of from 20° to 50° C. in the presence of a catalyst such asRaney nickel, palladium-on-charcoal, palladium black, palladiumhydroxide, or the like, under a hydrogen pressure of from 1 to 5atmospheres.

Transformation 3→4 is accomplished in a solvent such as pyridine ordichloromethane, chloroform, or the like with p-toluenesulfonylchloride, p-toluenesulfonic anhydride, or the like in the presence of abase such as Et₃ N, iPr₂ NEt, pyridine, 4-dimethylaminopyridine, or thelike, at a temperature of from -15° C. to +10° C. for from 24 hours to10 days to yield the C-3 tosylate, which upon treatment, in a solventsuch as ethanol, methanol, or the like, with alcoholic base, such asethanolic sodium hydroxide, ethanolic potassium hydroxide, methanolicsodium hydroxide, methanolic potassium hydroxide, or the like, followedby treatment with an alkali azide, such as lithium azide, sodium azide,potassium azide, or the like in the presence of ammonium chloride at atemperature of from 50° C. to 100° C. from 1 hour to 24 hours yields theazide 4.

Treatment of 4 in a solvent such as dichloromethane, chloroform, or thelike with trifluoromethanesulfonyl chloride, trifluoromethanesulfonicanhydride, or the like in the presence of a base such as Et₃ N, iPr₂NEt, pyridine, 4-dimethylaminopyridine or the like at a temperature offrom -76° C. to 0° C. for from 20 minutes to 2 hours, followed bytreatment with a brominating agent, such as lithium bromide, sodiumbromide, tetraethylammonium bromide, tetra-n-butylammonium bromide orthe like in a solvent such as, dichloromethane, acetonitriletetrahydrofuran, dimethylformamide, or the like at a temperature of from20° C. to 100° C. for from 30 minutes to 5 hours, yields the4-bromo-4-deoxy sugar 5 which upon treatment with sodium cyanide,potassium cyanide (in the presence or absence of a crown ether),tetraethylammonium cyanide, tetra-n-butylammonium cyanide,tetraethylammonium chloride-sodium cyanide, or the like in a solventsuch as dichloromethane, acetonitrile, tetrahydrofuran,dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, or thelike at a temperature of from 30° C. to 150° C. for from 15 minutes to24 hours yields compound 6.

In words relative to the Diagram I, above, the transformation 6→7 isaccomplished by treating 6 in a mineral acid such as hydrochloric acid,sulfuric acid, or the like with an alkanethiol having 1-6 carbon atoms,such as methanethiol, ethanethiol, propanethiol, or the like, or analkanedithiol, such as 1,2-ethanedithiol, 1,3-propanedithiol, or thelike at a temperature of from 0° to 30° C. for from 30 min. to 24 hours.The value of R is determined by the identity of the thiol taken inreaction. Compound 6 is disclosed and claimed in previously incorporatedby reference, concurrently filed U.S. patent application (16629). Thepreparation of 6 is given below.

Alcoholysis 7→8 is accomplished by treating 7 either (a) in an alcoholsuch as methanol, ethanol, propanol, or the like with an alkalialkoxide, such as sodium methoxide, sodium ethoxide, sodium propoxide,or the like, at a temperature of from 0° to 30° C. for from 1 to 24hours, followed by neutralization with a cation-exchange resin in the H⁺cycle, such as Amberlite IR-120(H⁺), Bio-Rad AG 50W, Dowex 50W, or thelike; or (b) in a solvent such as diethyl ether, dichloromethane,chloroform, or the like with an alcohol, such as methanol, ethanol,propanol or the like saturated at 0° C. with dry hydrogen chloride gas,at a temperature of from 0° to 30° C. for from 2 to 24 hours, followedby hydrolysis at 0° C. The value of R¹ is determined by the identity ofthe alcohol taken in reaction.

Conversion of azido ester 8 into amino ester 9 is accomplished bytreating 8 in a solvent such as methanol, ethanol, ethyl acetate, or thelike, at a temperature of from 20° to 50° C. in the presence of acatalyst such as palladium-on-charcoal, palladium black, palladiumhydroxide, palladium-on-barium sulfate, platinum oxide or the like undera hydrogen pressure of from 1 to 5 atmospheres.

The transformation 9→10 establishes the protecting group R². The mostpreferred protecting groups R² are triorganosilyl groups such ast-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl,isopropyldimethylsilyl, and the like. Typically, silylation isaccomplished by treating 9 with the corresponding triorganosilylchloride in a solvent such as dimethylformamide,hexamethylphosphoramide, acetonitrile, tetrahydrofuran, and the like ata temperature of from -20° to 80° C. for from 0.5 to 24 hours in thepresence of a base such as triethylamine, diisopropylethylamine, orimidazole.

The resulting species 10 in a solvent such as ether, THF, DME, or thelike is treated with EtMgBr, MeMgI, MgBr, t-BuMgCl, or the like at atemperature of from -40° to 50° C. for from 1 to 72 hours to provideazetidinone 11.

The transformation 11→12 is accomplished by treating 11 in a solventsuch as aqueous THF, aqueous acetone, aqueous acetonitrile, aqueousp-dioxane, or the like with a Lewis acid, such as mercuric oxide,mercuric chloride, boron trifluorideetherate, thallium trinitrate,silver tetrafluoroborate, or the like at a temperature of from 0° to 50°C. for from 1 to 24 hours.

In the foregoing word description of the above schematic reactiondiagram for the total synthesis of thienamycin, it is to be understoodthat there is considerable latitude in selection of precise reactionparameters. Suggestion of this latitude and its breadth is generallyindicated by the enumeration of equivalent solvent systems, temperatureranges, protecting groups, and range of identities of involved reagents.Further, it is to be understood that the presentation of the syntheticscheme as comprising distinct steps in a given sequence is more in thenature of a descriptive convenience than as a necessary requirement; forone will recognize that the mechanically dissected scheme represents aunified scheme of synthesis and that certain steps, in actual practice,are capable of being merged, conducted simultaneously, or effected in areverse sequence without materially altering the progress of synthesis.

The following examples recite a precise scheme of total synthesis. It isto be understood that the purpose of this recitation is to furtherillustrate the total synthesis and not to impose any limitation.

EXAMPLE 1 Step A: Preparation of3-azido-4-C-cyano-2,3,4,6-tetradeoxy-D-arabino-hexose trimethylenedithioacetal ##STR8##

Methyl 3-azido-4-C-cyano-2,3,4,6-tetradeoxy-α-D-arabino-hexopyranoside(675 mg, 3.44 mmol) is treated with concentrated hydrochloric acid (150ml) for 5 min at room temperature, at which time 1,3-propanedithiol(0.69 ml, 6.87 mmol) and sufficient methanol to achieve solution areadded. After the reaction mixture is stirred for 1 hour at roomtemperature, the methanol is removed by evaporation under vacuum, andthe product is extracted with dichloromethane. The combined organicextracts are evaporated under vacuum, and the residue is chromatographedon a column of silica gel (Merck No. 7734) (1:1 diethyl ether-hexane) toyield 890 mg (95%) of the trimethylene dithioacetal as a whitecrystalline solid; ¹ H NMR (300 MHz, CDCl₃): 1.50 (d, C--CH₃), 1.76 (d,OH-5, J_(OH), H- 5 5 Hz), 1.92 (m, 1H, dithiane H-4), 2.07 (septet,H-2), 2.17 (m, 1H, dithione H-4'), 2.27 (septet, H-2'), 2.68 (dd, H-4,J₃,4; 4,5 3.2, 9 Hz), 2.84-3.00 (m, 4H, dithiane H-3's), 4.14-4.26 (m,2H, H-1, H-5), 4.34 ppm (m, H-3); mass spectrum m/e 272(M).

Step B: 3-Azido-4-C-carbomethoxy-2,3,4,6-tetradeoxy-D-arabino-hexosetrimethylene dithioacetal ##STR9##

Dry hydrogen chloride gas is bubbled for 1 hour through a solution of3-azido-4-C-cyano-2,3,4,6-tetradeoxy-D-arabino-hexose trimethylenedithioacetal (885 mg, 3.25 mmol) in diethyl ether (5 ml) and absolutemethanol (5 ml) cooled in an ice-bath. The solution is then allowed tostand overnight at room temperature and evaporated under vacuum. Theresidue is taken up in dichloromethane, washed with saturated sodiumhydrogen carbonate solution, and evaporated. The resulting material ischromatographed on a column of silica gel (Merck No. 7734) (10:1 diethyletherhexane) to afford 744 mg (75%) of the desired azido estertrimethylene dithioacetal; IR (CHCl₃): ##STR10## 2095 (N₃); ¹ H NMR (300MHz, CDCl₃): 3.79 (s, 3H, CO₂ CH₃).

Step C: 3-Amino-4-C-carbomethoxy-2,3,4,6-tetradeoxy-D-arabino-hexosetrimethylene dithioacetal ##STR11##

A mixture of3-azido-4-C-carbomethoxy-2,3,4,6-tetradeoxy-D-arabino-hexosetrimethylene dithioacetal (736 mg, 2.41 mmol) and 5%palladium-on-charcoal (300 mg) in methanol (20 ml) is hydrogenated at apressure of 1 atmosphere for 5 hours at room temperature. The catalystis then removed by filtration through Celite and the filtrate evaporatedand dried in vacuo to give TLC-chromatographically-homogeneousninhydrin-positive amino ester trimethylene dithioacetal; yield 653 mg(97%);

IR (CHCl₃); 1733 (C═O); ¹ H NMR (CDCl₃, 300 MHz): 3.80 (s, 3H, CO₂ CH₃).

Step D:3α-[(1'R)-hydroxyethyl]-4β-[2',2'-(1,3-propanedithio)-ethyl]-2-azetidinone##STR12##

t-Butyldimethylchlorosilane (737 mg, 4.89 mmol) is added in one portionto a solution of3-amino-4-C-carbomethoxy-2,3,4,6-tetradeoxy-D-arabinohexose trimethylenedithioacetal (651 mg, 2.33 mmol) and triethylamine (0.68 ml, 4.89 mmol)in anhydrous dimethylformamide (10 ml) at 0° C. After 15 min at 0° C.,the reaction mixture is stirred at room temperature for 24 hours. Mostof the solvent is removed by evaporation under vacuum. The residue ispartitioned between diethyl ether (75 ml) and water. The ethereal phaseis washed with 2.5N hydrochloric acid (15 ml), water (3×15 ml), andbrine. The organic phase is dried (magnesium sulfate) and evaporated invacuo to afford3-(t-butyldimethylsilyl)-amino-4-C-carboxmethoxy-5-O-t-butyldimethylsilyl-2,3,4,6-tetra-deoxy-D-arabino-hexosetrimethylene dithioacetal.

Anhydrous diethyl ether (6 ml) is added to the flask containing thedisilyl derivative. The resulting solution is stirred under a nitrogenatmosphere with ice-bath cooling. Ethereal ethyl magnesium bromide (0.80ml of a 2.94M solution, 2.35 mmol) is added at 0° C., and the mixture isstirred overnight at room temperature. The mixture is then cooled in anice-methanol bath while ammonium chloride-saturated 2N hydrochloric acid(2.5 ml) is slowly added with stirring. The resulting mixture is dilutedwith ethyl acetate (2.5 ml) and water (2.5 ml) and the layers areseparated. The aqueous portion is extracted with more ethyl acetate (3×5ml). The combined organic solution is washed with water (5 ml), 5%aqueous sodium bicarbonate solution (3 ml), water (3 ml), and brine,dried (magnesium sulfate), and filtered. The material obtained uponevaporation of the filtrate is purified by chromatography on silica gel(Merck No. 7734) to yield the desired 2-azetidinone trimethylenedithioacetal; yield 144 mg.

Step E: 3α-[(1'R)-hydroxyethyl]-4β-(2'-oxoethyl)-2-azetidinone ##STR13##

To a suspension of red mercuric oxide (3.5 equiv.) and borontrifluoride-etherate (3 equiv) in 17% aqueous acetone (3.5 ml) is addedwith stirring under nitrogen a solution of3α-[(1'R)-hydroxyethyl]-4β-[2',2'-(propanedithio)-ethyl]-2-azetidinone(141 mg, 0.57 mmol) in tetrahydrofuran (1 ml). After stirring for 24hours, water (1.5 ml) and acetone (3 ml) are added and the mixtureneutralized with sodium bicarbonate. The precipitate is filtered, thefiltrate concentrated and extracted several times with chloroform. Theorganic extracts are washed with brine, dried (magnesium sulfate), andevaporated in vacuo to afford 63 mg (70%) of the desired aldehydeazetidinone.

EXAMPLE 2 Process for preparing Methyl3-azido-4-C-cyano-2,3,4,6-tetradeoxy-α-D-arabinohexopyranoside

STEP A

Methyl 2,6-dideoxy-3-O-(p-toluenesulfonyl)-α-D-arabinohexopyranoside

To a solution of methyl 2,6-dideoxy-α-D-arabino-hexopyranoside (6.3 g,38.8 mmol) in pyridine (200 ml) at 0° C. is added freshly recrystallizedp-toluenesulfonyl chloride (7.6 g, 39.9 mmol). The mixture is kept 5days at 0° C., at which time additional p-toluenesulfonyl chloride (1.9g) is added. After 3 days at 5° C., the mixture is poured intoice-water, extracted several times with dichloromethane, the combinedorganic extracts evaporated under vacuum, coevaporated several timeswith toluene, and chromatographed on silica gel (Merck No. 7734) (1:2diethyl ether-petroleum ether, b.p. 35°-60° C.) to yield 8.5 g (69%) ofthe product as a solid; 'H NMR (300 MHz, CDCl₃): 1.30 (d, C--CH₃), 1.83(td, H-2ax, J-H-1, H-2ax, 3.5 Hz, J H2eq, H2ax 12.8 Hz), 2.09 (m, H-2eq,J H-1, H-2eq 1.1 Hz, J H-2 eq, H-3 5.5 Hz), 2.46 (s, ArCH₃), 2.53 (d,OH), 3.27 (s, OCH₃), 3.32 (td, H-4, J_(H-4-H-5) =J_(H-4), H-3 =8.8 Hz),3.65 (m, H-5), 4.68 (broad d, H-1), 4.74 (ddd, H-3), 7.38 (d, 2H, Ar),7.85 ppm (d, 2H, Ar); mass spectrum m/e 285 (M--OCH₃), 272 (M--CH₃ CHO).

Anal. C, H, S.

STEP B

Methyl 3-Azido-2,3,6-tredeoxy-α-D-arabino-hexopyranoside

To a solution of methyl2,6-dideoxy-3-O-(p-toluenesulfonyl)-α-D-arabino-hexopyranoside (8.4 g,26.6 mmol) in absolute ethanol (80 ml) is added phenolphthalein (as anindicator) and subsequently dropwise at 60° C. saturated ethanolicsodium hydroxide until color persists for ˜10 minutes. The reactionmixture is then cooled to 10° C., the precipitated sodium tosylateremoved by filtration, the filtrate brought to pH 7 with 2N hydrochloricacid. Sodium azide (4.9 g) and ammonium chloride (2.9 g) are then added,and the mixture is stirred overnight at reflux temperature. Afterconcentration, the residue is partitioned between dichloromethane andwater, the aqueous layer extracted with dichloromethane, the combinedorganic extracts evaporated under vacuum, and chromatographed on silicagel (Merck No. 7734) (30:1 chloroformethyl acetate) to afford the pureproduct as a colorless syrup; yield 3.7 g (74%); 'H NMR (300 MHz,CDCl₃): 1.30 (d, C--CH₃), 1.73 (td, H-2ax, J_(H-1),H-2ax 3.6 Hz), 2.17(m, H-2eq, J_(H-1), H-2eq 1.2 Hz, J_(H-2eq), H-3 5 HZ), 3.14 (t, H-4,J-_(H-3), H-4 =J_(H-4), H-5 =9 Hz), 3.34 (s, OCH₃), 3.63-3.79 (m,H-3,5), 4.75 (broad d, H-1); mass spectrum m/e 187 (M), 156 (M--OCH₃),145 (M--N₃), 143 (M--CH₃ CHO).

STEP C

Methyl 3-azido-4-bromo-2,3,4,6-tetradeoxy-α-D-lyxohexopyranoside

To a solution of methyl3-azido-2,3,6-trideoxy-α-D-arabino-hexopyranoside (3.6 g, 19.2 mmol) indichloromethane (100 ml) cooled in an ice-bath are added pyridine (2 ml)and dropwise a solution of trifluoromethanesulfonic anhydride (3.2 ml,19.0 mmol) in dichloromethane (25 ml). After stirring for 10 minutes at0° C. with exclusion of moisture, additional pyridine (2 ml) andtrifluoromethanesulfonic anhydride (2.6 ml) are added. After 10 minutesat 0° C., the reaction mixture is diluted with dichloromethane (130 ml)and poured into a separatory funnel containing ice-water. The organiclayer is separated and washed with cold N hydrochloric acid, saturatedsodium hydrogencarbonate, water, and dried (sodium sulfate). Evaporationunder vacuum gives the 4-trifluoromethanesulfonate that is dissolved indry acetonitrile (50 ml) and treated with tetra-n-butylammonium bromide(12.7 g, 39.4 mmol) for 1 hour at 40° C. The reaction mixture isconcentrated, the residue partitioned between dichloromethane and water,the organic layer evaporated under vacuum and the resulting syrupchromatographed on a column of silica gel (Merck No. 7734) (1:2dichloromethane-hexane) to yield 3.65 g (76%) of the bromide; 'H NMR(300 MHz, CDCl₃): 1.32 (d, C--CH₃), 1.90 (dd, H-2eq), 2.20 (td, H-2ax),3.36 (s, OCH₃), 3.84-4.00 (m, H-3,5), 4.27 (d, H-4), 4.86 ppm (d, H-1);mass spectrum m/e 250 (M).

STEP D

Methyl 3-azido-4-C-cyano-2,3,4,6-tetradeoxy-α-D-arabino-hexopyranoside

To a solution of methyl3-azido-4-bromo-2,3,4,6-tetradeoxy-α-D-lyxo-hexopyranoside (3.5 g, 14.0mmol) in freshly distilled acetonitrile (75 ml) is addedtetra-n-butylammonium cyanide (7.5 g, 28.0 mmol). The reaction mixtureis stirred for 1 hour at 50° C., cooled, partially concentrated (25 ml),diluted with dichloromethane (250 ml), washed with water (3×), dried(sodium sulfate), and evaporated under vacuum. The residue ischromatographed on a column of silica gel (Merck No. 7734) (1:10 diethylether-hexane) to yield 687 mg (25%) of the desired cyanide as acolorless syrup; 'H NMR (300 MHz, CDCl₃): 1.42 (d, C--CH₃), 1.60 td,H-2ax, J_(H-1),H-2ax 3.5 Hz), 2.21 (m, H-2eq, J_(H-1), H-2eq 1.2 Hz,J_(H-2eq), H-3 5 Hz), 2.26 (t, H-4, J_(H-3), H-4 =J_(H-4), H-5 =10.8Hz), 3.36 (s, OCH₃), 3.92-4.06 (m, H-3,5), 4.85 (broad d, H-1); massspectrum m/e 165 (M--OCH₃), 154 (M--N₃), 152 (M--CH₃ CHO).

What is claimed is:
 1. A compound selected from the group consisting of ##STR14## wherein R and R¹ are each selected from alkyl having 1-6 carbon atoms. 